Cutaneous malignant melanoma is one of the most common and deadliest cancers, and its incidence continues to rise to epidemic proportions, to the extent that it is now the most prevalent cancer among women under forty. The solar ultraviolet radiation (UV) is widely accepted to be the greatest risk factor for melanoma; however, the underlying molecular mechanisms are incompletely understood. Identification of the causal UV-induced mutations has long been the major thrust in the field, but importance of non-mutational and microenvironmental mechanisms, for example inflammation and immunoevasion/immunosuppression, remains severely understudied. Here we have proposed a hypothesis that Interferon-gamma (IFNg), which is conventionally associated with anti-tumor immunesurveillance mechanisms, plays a pro-tumorigenic role in the context of UV-induced melanomagenesis. The proposed research will elucidate the mechanisms of the pro-melanomagenic effects of IFNg. In Specific Aim 1, the specific mechanisms of the pro-metastatic and drug resistance effects of IFNg treatment on melanoma cells via activation of Signal Transducer and Activator of Transcription 3 (STAT3) and Microphthalmia Associated Transcription Factor (MITF) will be tested. UV- induced melanomagenesis experiments will be performed in the inducible BrafV600E (BrafCA)mouse model of UV-induced melanomagenesis, in which the IFNg signaling has been blocked via melanocyte-specific knockout of IFNg-Receptor. Specific Aim 2 will characterize the IFNg-secreting (IFNg+) macrophages that are recruited to the skin microenvironment by erythemal UV exposure, and will validate this novel subpopulation of macrophages as a biomarker of susceptibility and prognosis of human melanoma. It will be determined whether genetic blockade of UV-induced macrophage influx into skin inhibits melanomagenesis. In Specific Aim 3, the role of IFNg-induced expression of the cytotoxic T-lymphocyte antigen 4 (CTLA4) in melanoma cells in the process of melanomagenesis will be investigated. It will be tested whether melanocytic expression of CTLA4 protects them from T-cell-mediated immunesurveillance, leading to immunoevasion and progression of melanoma, and whether genetic ablation of Ctla4 specifically in the melanocyte compartment inhibits UV-induced melanomagenesis in the BrafCA mouse model. Finally, CTLA4 expression on melanoma cells will be investigated as a predictive biomarker of response to anti-CTLA4 immunotherapy in clinical samples of human melanoma patients. The overall goal of the proposed project is to investigate the IFNg pathway as a novel microenvironmental mechanistic link to UV-induced melanoma susceptibility and disease progression.